Interleukin (IL)-1 is a key mediator of neuroinflammation via actions of two agonists IL-1α and β that bind to the IL-1 type I receptor (IL-1RI), and are thought to trigger identical responses. However, evidence suggests that IL-1α and β may have differential actions in the central nervous system (CNS). The objective of this study was to test the hypothesis that IL-1α and β differentially regulate the expression of IL-6 and chemokines KC, IP-10 and MCP-1 in primary neurones. Here we demonstrate that, whilst IL-1β induced significant synthesis of IL-6 in neurones, IL-1α had no effect. In contrast, IL-1α and β induced strong synthesis and constitutive release of chemokines KC, IP-10 and MCP-1 from neurones, and these responses were IL-1RI-dependent. Whilst IL-1β-induced IL-6 synthesis was dependent on the nSMase/Src kinase signalling cascade, specific inhibitors of nSMase (3-OMS) and Src kinase (PP2) failed to inhibit IL-1α- and IL-1β-induced chemokines synthesis, suggesting the existence of alternative signalling pathway(s) in neurones.